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Sport24.co.za | Jordaan admits PSL decision is complicated

Danny Jordaan says it would be massively complicated to ensure the safety of supporters should the PSL return while Covid-19 is still prevalent in South Africa.




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Watch Meet the Smiths Online | Season 1 Full Episodes Video Streaming & Torrent Search

Meet the Smiths Synopsis Meet the Smiths is a scripted reality television series produced by TBS that premiered in April of 2015. Meet the Smiths follows the daily lives of Kenny Smith, an NBA analyst for TNT and his wife Gwendolyn Osborne-Smith, a model for The Price is Right. The couple has five children together […]




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A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning [Molecular Biophysics]

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.




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Webinar: The Environmental Crisis in the MENA Region – Impacts and Mitigation

Research Event

16 April 2020 - 11:30am to 12:30pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Glada Lahn, Senior Research Fellow, Energy, Environment and Resources Programme, Chatham House
Greg Shapland, Associate Fellow, Middle East and North Africa Programme, Chatham House 
Moderator: Sanam Vakil, Deputy Director and Senior Research Fellow, Middle East and North Africa Programme, Chatham House

The event will be livestreamed on the MENA Programme Facebook page.

Climate and environmental issues have largely been marginalized in discussions about the Middle East and North Africa region and yet are critical to peace and security. In this webinar, experts will explore mounting pressures including those related to water (reduced, less reliable and more polluted sources), extreme temperatures, air pollution, land degradation and sea-level rise. Panelists will discuss the potential impact of worsening environmental conditions and what the region's governments can do to protect the health and livelihoods of their peoples.

This webinar is part of the Chatham House MENA Programme's Online Event Series and will be held on the record.

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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The Committee to Protect Journalists named winner of the Chatham House Prize 2018

8 October 2018

The Committee to Protect Journalists (CPJ) has been voted the winner of this year’s Chatham House Prize. 

The Chatham House Prize is presented annually to the person, persons or organization deemed by members of the Royal Institute of International Affairs to have made the most significant contribution to the improvement of international relations in the previous year.

The CPJ has been recognized for its efforts in defending the right of journalists to report the news without fear of reprisal, at a time when the free press is under serious pressure in many parts of the world.

Highlights of the work of the CPJ during 2017 include the launch of the US Press Freedom Tracker documenting attacks on press freedom in the US and the launch of its Free the Press campaign to raise awareness of journalists imprisoned on anti-state charges around the world. In addition, last year its advocacy helped secure the early release from prison of at least 75 journalists worldwide and helped to win convictions in the murders of six reporters, including Marcos Hernández Bautista in Mexico and Syrian editor Naji Jerf, who was killed in Turkey.

In a climate where the term ‘fake news’ is used to discredit much reporting, the CPJ has robustly supported the fourth estate’s role in contributing to a sustainably secure, prosperous and just world.

Events

The Chatham House Prize 2018 was awarded in a ceremony on Wednesday 28 November at Chatham House in London. The executive director of the committee, Joel Simon, accepted the award and spoke about the importance of safeguarding journalism and free speech, followed by a discussion about the challenges of reporting today with a panel of journalists who have faced these pressures in their work.

Nominees

The nominees for the Chatham House Prize 2018 were:

About the Chatham House Prize

The Chatham House Prize is presented to the person, persons or organization deemed by members of Chatham House to have made the most significant contribution to the improvement of international relations in the previous year.

The selection process is independent, democratic and draws on the deep knowledge of Chatham House's research teams, making the Prize a distinctive and unique award in the field of international affairs.

A short-list of nominees is selected by the institute's three presidents from a longer list submitted by the research programmes and departments in their areas of expertise. The recipient is then determined by Chatham House's broad membership base on a one-member, one-vote basis. The award is presented on behalf of the institute's patron, Her Majesty the Queen, representing the non-partisan and authoritative character of the Prize.

The Chatham House Prize was launched in 2005. Previous recipients of the Prize include former Colombian president Juan Manuel Santos, former president of Ghana John Kufuor, Médecins Sans Frontières and Melinda Gates, co-founder of the Bill and Melinda Gates Foundation.

For more information, please contact:

Chatham House press office
Email: pressoffice@chathamhouse.org
Phone: +44 (0)207 957 5739

CPJ Communications Associate 
Beatrice Santa-Wood
Email: press@cpj.org
Phone: +1 212 300 9032




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Press Briefing: The 2014 NATO Summit

Invitation Only

28 August 2014 - 10:00am to 11:00am

Chatham House, London

Event participants

Robin Niblett, Director, Chatham House; Chair, NATO Group of Policy Experts
Xenia Wickett, Project Director, US; Acting Dean, Academy for Leadership in International Affairs, Chatham House

Chair
Paola Totaro, President, Foreign Press Association

With the NATO summit in Wales taking place against a backdrop of instability in Ukraine and the end of NATO combat operations in Afghanistan, the panel will discuss these and other major challenges facing the alliance. 

This event will be held in conjunction with the Foreign Press Association.

Read more on NATO: Charting the Way Forward >>>

Department/project

Press Office

+44 (0)20 7957 5739




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Advancing the 2014 NATO Summit Deliverables

Invitation Only Research Event

30 October 2014 - 1:15pm to 31 October 2014 - 5:00pm

Chatham House, London

Event participants

Xenia Wickett, Project Director, US; Dean, Academy for Leadership in International Affairs, Chatham House
Dr Christian Moelling, International Security Division Associate, SWP-Berlin

The NATO Summit, held in September in Newport, Wales, was a way point in the larger strategic vision for NATO over the coming decade. The deliverables that the leaders laid out must now been acted upon. NATO and its member states must find ways to more effectively harness their significant resources to meet the challenges ahead, from the ongoing conflicts in Ukraine and the Middle East, to the longer term threats posed by cyber-attack and energy insecurity.

The event will bring together senior representatives from a number of the NATO member states, NATO partners and external experts from industry, the media and the think-tank and academic communities, to discuss how best to move the deliverables forward, and how to most effectively work together in so doing.

This is the first of two workshops being held in collaboration with SWP-Berlin.

Department/project

Richard Gowing

Programme Administrator
+44 (0)20 7389 3270




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Implementing the NATO Wales Summit: From Strategy to Action

Invitation Only Research Event

26 February 2015 - 1:00pm to 27 February 2015 - 5:00pm

German Institute for International and Security Affairs, Berlin, Germany

Event participants

Xenia Wickett, Project Director, US; Dean, The Queen Elizabeth II Academy for Leadership in International Affairs, Chatham House
Dr Christian Moelling, International Security Division Associate, SWP-Berlin

The NATO Summit, held in September 2014 in Newport, Wales, was a waypoint in the larger strategic vision for NATO over the coming decade. As the alliance continues to confront challenges on its eastern and southern frontiers, it must find ways to adapt its strategy for more effective responses, while also staying ahead of emerging threats and risks. 

The event will bring together senior representatives from a number of the NATO member states, NATO partners and external experts from industry, the media and the think-tank and academic communities, to examine what NATO member states have done thus far to move the deliverables forward, and how to most effectively work together in continuing to do so. 

Attendance at this event is by invitation only.

This is the second of two workshops held in collaboration with SWP-Berlin; the first took place at Chatham House in October 2014.

Event attributes

External event




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Allies Beware: Americans Support a More Limited Role for the US

12 May 2016

Bruce Stokes

Associate Fellow, US and the Americas Programme (based in the US)

Xenia Wickett

Former Head, US and the Americas Programme; Former Dean, The Queen Elizabeth II Academy for Leadership in International Affairs
While not as isolationist or unilateralist as some campaign rhetoric might suggest, new polling shows the American public broadly supports less engagement with the rest of the world.

2016-05-11-US-Philippines.jpg

US military personnel take part in joint military exercises with the Philippines, Australia and Japan in Crow Valley on 14 April 2016. Photo by Getty Images.

While the American election cycle could be perceived as an occasionally amusing distraction, the rise of new factions and sentiments among the electorate will have an impact not just in America’s domestic politics but also with respect to its role in the world. Recent polling by the Pew Research Center shows clearly the desire among many Americans for a different international engagement for the US, one that could have significant implications for America’s allies.

Polling

To date, the campaign rhetoric of both the Republican and Democratic contenders for the White House has raised questions about America’s continuing global commitment.

But what does the public think? The Pew Research Center has recently released its periodic survey of how Americans view America’s place in the world. The results suggest that stereotypes of Americans’ isolationism or protectionism do not capture the nuance in public sentiment. Wariness of international engagement coexists with assertiveness on some issues and a belief that the US is a force for good in the world. And these views often divide along partisan lines and between generations.

A majority of Americans (57%) think the U.S. should deal with its own problems and let other countries deal with theirs as best they can, a sentiment that has increased from 46% in 2010. Moreover, roughly two-thirds say ‘we should not think so much in international terms but concentrate more on our own national problems’. In part this may be the case because a plurality of Americans thinks the United States does too much (41% too much, 27% too little) in helping solve world problems.

The fact that six-in-ten Americans believe that problems in the world would be even worse without US involvement will not reassure many non-Americans who care deeply about how and where the US is engaged, not just that it is.

American isolationism is a partisan affair. Republicans (62%) are far more likely than Democrats (47%) to voice the view that the US should deal with its own problems. Notably, about two-thirds of registered Republicans or Republican-leaning independents who favour Donald Trump (68%) express such isolationist sentiments, as do more than half of the Democratic backers of Sen. Bernie Sanders (54%). At the same time, over half of registered Democrats and Democratic-leaning independents who favour Hillary Clinton (52%) believe the US should help other countries deal with their problems.

The US has often been seen by its allies as acting in a unilateralist fashion, but the polling is more nuanced than this. About half (51%) believe that the US should take into account the views of its major allies when deciding its foreign policies. However, of more concern for America’s allies (and potentially adversaries), roughly four-in-ten (42%) believe Washington should go it alone in international matters.

Despite Trump’s criticisms, 53% of the American public holds a positive view of NATO and 77% voice the view that US membership in the security alliance has been a good thing for the United States.

In addition to some wariness with regards to engaging internationally in security arenas, Americans are also generally wary of global economic engagement – protectionist sentiment is rising. Only 44% believe such US involvement is a good thing; more (49%) say such engagement is bad, lowering wages and costing jobs. These views also differ along partisan lines with more on the right than left thinking US involvement in the world economy has been a bad thing. Trump supporters are even more against economic globalization.

Rising scepticism

The results do not show an unambiguous move towards more American isolationism or unilateralism. But the trends broadly show that the American public is moving towards, as President Obama put it in 2012, a focus on ‘nation building at home’. It should come as no surprise – President Obama has presided over a period in which the US has increasingly limited its extraterritorial ambitions to those that more directly affect its vital national interests. It is therefore worth noting that this more limited engagement is one that is, broadly, supported by the public on both sides of the aisle.

There are, as have been noted, partisan differences. But the next president will govern over all Americans not just those from their own party. They will have to function in the context of an American public, the majority of whom wants the US to deal with its own problems, letting other countries manage as best they can. While who becomes president clearly matters – they have the capacity to lead their populations in certain directions - the rising scepticism among many Americans for investing in the globalized world will resonate regardless of who takes office.

The implications for America’s allies are significant. For those issues that are not directly of concern to the United States, longstanding partners are going to have to find ways to manage on their own or with less American support. And even on those issues that are of direct national interest, they might find the US less sensitive to their interests and concerns. This could hold true not just in the realm of security but on economic issues also – if America becomes more protectionist, others will surely follow.  

Many of America’s allies have perceived the United States to be an unreliable ally in recent years. Asian partners, such as Japan and South Korea, have started to take more responsibility for their own security and are working to build additional partnerships with neighbours. European allies have been, at times, disappointed by what they perceive to be a less engaged America, such as in Libya and Syria. If the next president follows the public majority, these allies will need to get used to this new role for the United States.

This article has been published jointly with Real Clear World.

To comment on this article, please contact Chatham House Feedback




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England and Australia Are Failing in Their Commitments to Refugee Health

10 September 2019

Alexandra Squires McCarthy

Former Programme Coordinator, Global Health Programme

Robert Verrecchia

Both boast of universal health care but are neglecting the most vulnerable.

2019-09-09-Manus.jpg

A room where refugees were once housed on Manus Island, Papua New Guinea. Photo: Getty Images.

England and Australia are considered standard-bearers of universal access to health services, with the former’s National Health Service (NHS) recognized as a global brand and the latter’s Medicare seen as a leader in the Asia-Pacific region. However, through the exclusion of migrant and refugee groups, each is failing to deliver true universality in their health services. These exclusions breach both their own national policies and of international commitments they have made.

While the marginalization of mobile populations is not a new phenomenon, in recent years there has been a global increase in anti-migrant rhetoric, and such health care exclusions reflect a global trend in which undocumented migrants, refugees and asylum seekers are denied rights.

They are also increasingly excluded in the interpretation of phrases such as ‘leave no one behind’ and ‘universal health coverage’, commonly used by UN bodies and member states, despite explicit language in UN declarations that commits countries to include mobile groups.

Giving all people – including undocumented migrants and asylum seekers – access to health care is essential not just for the health of the migrant groups but also the public health of the populations that host them. In a world with almost one billion people on the move, failing to take account of such mobility leaves services ill-equipped and will result in missed early and preventative treatment, an increased burden on services and a susceptibility to the spread of infectious disease.

England

While in the three other nations of the UK, the health services are accountable to the devolved government, the central UK government is responsible for the NHS in England, where there are considerably greater restrictions in access.

Undocumented migrants and refused asylum seekers are entitled to access all health care services if doctors deem it clinically urgent or immediately necessary to provide it. However, the Home Office’s ‘hostile environment’ policies towards undocumented migrants, implemented aggressively and without training for clinical staff, are leading to the inappropriate denial of urgent and clearly necessary care.

One example is the case of Elfreda Spencer, whose treatment for myeloma was delayed for one year, allowing the disease to progress, resulting in her death.

In England, these policies, which closely link health care and immigration enforcement, are also deterring people from seeking health care they are entitled to. For example, medical bills received by migrants contain threats to inform immigration enforcement of their details if balances are not cleared in a certain timeframe. Of particular concern, the NGO Maternity Action has demonstrated that such a link to immigration officials results in the deterrence of pregnant women from seeking care during their pregnancy.

Almost all leading medical organizations in the United Kingdom have raised concerns about these policies, highlighting the negative impact on public health and the lack of financial justification for their implementation. Many have highlighted that undocument migrants use just and estimated 0.3% of the NHS budget and have pointed to international evidence that suggests that restrictive health care policies may cost the system more.

Australia

In Australia, all people who seek refuge by boat are held, and have their cases processed offshore in Papua New Guinea (PNG) and Nauru, at a cost of almost A$5 billion between 2013 and 2017. Through this international agreement, in place since 2013, Australia has committed to arrange and pay for the care for the refugees, including health services ‘to a standard of care broadly comparable to that available to the general Australian community under the public health system’.

However, the standard of care made available to the refugees is far from comparable to that available to the general population in Australia. Findings against the current care provision contractor on PNG, Pacific International Hospital, which took over in the last year, are particularly damning.

For instance, an Australian coroner investigating the 2014 death from a treatable leg infection of an asylum seeker held in PNG concluded that the contractor lacked ‘necessary clinical skills’, and provided ‘inadequate’ care. The coroner’s report, issued in 2018, found the company had also, in other cases, denied care, withheld pain relief, distributed expired medication and had generally poor standards of care, with broken or missing equipment and medication, and services often closed when they were supposed to be open.

This has also been reiterated by the Royal Australasian College of Physicians, which has appealed to the Australian government to end its policies of offshore processing immediately, due to health implications for asylum seekers. This echoes concerns of the medical community around the government’s ongoing attempts to repeal the ‘Medivac’ legislation, which enables emergency medical evacuation from PNG and Nauru.

Bad policy

Both governments have signed up to UN Sustainable Development Goals commitment to ‘safe and orderly migration’, an essential component of which is access to health care. The vision for this was laid out in a global action plan on promoting the health of refugees and migrants, agreed by member states at the 2019 World Health Assembly.

However, rather than allow national policies to be informed by such international plans and the evidence put forward by leading health professionals and medical organizations, the unsubstantiated framing of migrants as a security risk and economic burden has curtailed migrant and refugee access to health care.

The inclusion of migrants and refugees within universal access to health services is not merely a matter of human rights. Despite being framed as a financial burden, ensuring access for all people may reduce costs on health services through prevention of costly later-stage medical complications, increased transmission of infections and inefficient administrative costs of determining eligibility.

Thailand provides an example of a middle-income country that recognized this, successfully including all migrants and refugees in its health reforms in 2002. Alongside entitling all residents to join the universal coverage scheme, the country also ensured that services were ‘migrant friendly’, including through the provision of translators. A key justification for the approach was the economic benefit of ensuring a healthy migrant population, including the undocumented population.

The denial of quality health services to refugees and undocumented migrants is a poor policy choice. Governments may find it tempting to gain political capital through excluding these groups, but providing adequate access to health services is part of both governments’ commitments made at the national and international levels. Not only are inclusive health services feasible to implement and good for the health of migrants and refugees, in the long term, they are safer for public health and may save money.




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Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells [Signal Transduction]

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.




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Analysis of the Subunit Composition of Complex I from Bovine Heart Mitochondria

Joe Carroll
Feb 1, 2003; 2:117-126
Research




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Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues

Roland Bruderer
May 1, 2015; 14:1400-1410
Research




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DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels [Cell Biology]

Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.




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The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining {alpha}-tubulin acetylation [Signal Transduction]

Kindlins are focal adhesion proteins that regulate integrin activation and outside-in signaling. The kindlin family consists of three members, kindlin-1, -2, and -3. Kindlin-2 is widely expressed in multiple cell types, except those from the hematopoietic lineage. A previous study has reported that the Drosophila Fit1 protein (an ortholog of kindlin-2) prevents abnormal spindle assembly; however, the mechanism remains unknown. Here, we show that kindlin-2 maintains spindle integrity in mitotic human cells. The human neuroblastoma SH-SY5Y cell line expresses only kindlin-2, and we found that when SH-SY5Y cells are depleted of kindlin-2, they exhibit pronounced spindle abnormalities and delayed mitosis. Of note, acetylation of α-tubulin, which maintains microtubule flexibility and stability, was diminished in the kindlin-2–depleted cells. Mechanistically, we found that kindlin-2 maintains α-tubulin acetylation by inhibiting the microtubule-associated deacetylase histone deacetylase 6 (HDAC6) via a signaling pathway involving AKT Ser/Thr kinase (AKT)/glycogen synthase kinase 3β (GSK3β) or paxillin. We also provide evidence that prolonged hypoxia down-regulates kindlin-2 expression, leading to spindle abnormalities not only in the SH-SY5Y cell line, but also cell lines derived from colon and breast tissues. The findings of our study highlight that kindlin-2 regulates mitotic spindle assembly and that this process is perturbed in cancer cells in a hypoxic environment.




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Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells [Signal Transduction]

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.




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Why Turkey’s Disapproval of the West’s Response to the Coup Has Limited Merit

10 August 2016

Fadi Hakura

Consulting Fellow, Europe Programme
Although Turks across the political and ideological spectrum are seething at the West’s apparently lukewarm condemnation of the abortive coup on 15 July, there are valid reasons behind the response.

2016-08-10-Turkey-coup-fallout.jpg

A Turkish flag attached to helium balloons as people gather to protest at Konak Square, Izmir during the July 15 failed military coup attempt. Photo by Getty Images

Signs of growing anger at the restrained denunciation of Pennsylvania-based Muslim cleric Fethullah Gulen - whose followers are thought to have played a key role in the attempted coup - are being vocalised more and more, but this criticism only shows part of the true picture.

It is true that prominent liberal Turkish intellectual Soli Ozel spoke for many when he criticised EU politicians and Western media for failing to recognise the “invaluable democratic resistance shown by all political parties in a parliament bombed by war planes”, as well as demonstrating “a lack of sensitivity, empathy and solidarity that cannot be easily digested” by not sending anyone from an EU institution to offer solidarity with the Turkish parliament.

The criticism is reasonable - officials from Western governments and regional institutions such as the Council of Europe exhibited unconditional solidarity with Ukraine during its bitter feud with Russia, which leads some to believe that Muslim-majority Turkey does not apparently deserve the same treatment as its neighbours also experiencing an unlawful attempt to seize control of the state.

Moral authority at risk

It is also right that the West should have censured the coup plotters more forcefully and built upon Turkey’s fragile unity to encourage the country to pursue further democratic reform. To quote former Swedish Prime Minister and Foreign Minister Carl Bildt: “Europe risks losing its moral authority if it does not appear particularly engaged in dealing with the coup itself.”

In addition, the EU’s strong criticism of Turkey but not France, for imposing a state of emergency and for temporarily suspending the European Convention on Human Rights, undeniably, smacks of double-standards.

However, some of the criticism falls short. To begin with, the West’s tepidity can be explained (though not wholly justified) by Erdogan’s abrasive behaviour at home and towards Western and international media.

Just three days after the coup, Erdogan threatened in his characteristically defiant tone to revive the controversial construction plans that sparked the 2013 Gezi Park protests, saying: “If we want to preserve our history, we must rebuild this historic [Ottoman-era barracks] structure, [and] we will rebuild it.”

It is also fair for Turkey to be reproached for the widespread crackdown against tens of thousands of suspected Gulenists in the aftermath of the coup. Even if it is conceivable that all 1,577 university deans who were forced to resign were Gulenists, this action will also have a lasting negative impact on the reputations and career prospects of academics unconnected to Gulen.

Fervour against Gulenism

The vigilance by the West is understandable given the Turkish government’s fervour against Gulenism in the immediate post-coup period. It would make no sense for the West to attack the coup and yet, at the same time, equivocate on flagrant violations of due process and human rights. Both efforts are mutually inclusive and identifying such violations has the greatest potential to encourage policy reversals or corrective measures.

Similarly understandable is the attention on Erdogan himself. He is the most formidable and powerful figure in a hierarchical and top-down political system, able to make fateful decisions with few effective checks and balances. He single-handedly replaced Ahmet Davutoglu as prime minister with Binali Yildirim in a clear breach of the Turkish constitution.

Despite Erdogan’s tactical attempts at embracing all the opposition parties apart from the pro-Kurdish Peoples’ Democratic Party (HDP), his refusal to renounce his ambition to transform Turkey into a powerful executive presidency indicates that this fragile political unity will not last.

Only the West has the wherewithal to moderate his policies by continuing to express its friendship with Turkey, whilst not shying away from closely monitoring, scrutinising and commenting on the post-coup developments.

Contact Chatham House Feedback

Join the conversation about this piece on Facebook




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Thematic review series: Lipid Posttranslational Modifications. Protein palmitoylation by a family of DHHC protein S-acyltransferases

David A. Mitchell
Jun 1, 2006; 47:1118-1127
Thematic Reviews




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S-Palmitoylation of the sodium channel Nav1.6 regulates its activity and neuronal excitability [Cell Biology]

S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions.




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The Western Balkans Before the Berlin Process Summit




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Chatham House Prize 2018: The Committee to Protect Journalists




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Proximity Dependent Biotinylation: Key Enzymes and Adaptation to Proteomics Approaches [Reviews]

The study of protein subcellular distribution, their assembly into complexes and the set of proteins with which they interact with is essential to our understanding of fundamental biological processes. Complementary to traditional assays, proximity-dependent biotinylation (PDB) approaches coupled with mass spectrometry (such as BioID or APEX) have emerged as powerful techniques to study proximal protein interactions and the subcellular proteome in the context of living cells and organisms. Since their introduction in 2012, PDB approaches have been used in an increasing number of studies and the enzymes themselves have been subjected to intensive optimization. How these enzymes have been optimized and considerations for their use in proteomics experiments are important questions. Here, we review the structural diversity and mechanisms of the two main classes of PDB enzymes: the biotin protein ligases (BioID) and the peroxidases (APEX). We describe the engineering of these enzymes for PDB and review emerging applications, including the development of PDB for coincidence detection (split-PDB). Lastly, we briefly review enzyme selection and experimental design guidelines and reflect on the labeling chemistries and their implication for data interpretation.




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Single-molecule level structural dynamics of DNA unwinding by human mitochondrial Twinkle helicase [Molecular Biophysics]

Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA–binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.




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A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning [Molecular Biophysics]

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.




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England and Australia Are Failing in Their Commitments to Refugee Health

10 September 2019

Alexandra Squires McCarthy

Former Programme Coordinator, Global Health Programme

Robert Verrecchia

Both boast of universal health care but are neglecting the most vulnerable.

2019-09-09-Manus.jpg

A room where refugees were once housed on Manus Island, Papua New Guinea. Photo: Getty Images.

England and Australia are considered standard-bearers of universal access to health services, with the former’s National Health Service (NHS) recognized as a global brand and the latter’s Medicare seen as a leader in the Asia-Pacific region. However, through the exclusion of migrant and refugee groups, each is failing to deliver true universality in their health services. These exclusions breach both their own national policies and of international commitments they have made.

While the marginalization of mobile populations is not a new phenomenon, in recent years there has been a global increase in anti-migrant rhetoric, and such health care exclusions reflect a global trend in which undocumented migrants, refugees and asylum seekers are denied rights.

They are also increasingly excluded in the interpretation of phrases such as ‘leave no one behind’ and ‘universal health coverage’, commonly used by UN bodies and member states, despite explicit language in UN declarations that commits countries to include mobile groups.

Giving all people – including undocumented migrants and asylum seekers – access to health care is essential not just for the health of the migrant groups but also the public health of the populations that host them. In a world with almost one billion people on the move, failing to take account of such mobility leaves services ill-equipped and will result in missed early and preventative treatment, an increased burden on services and a susceptibility to the spread of infectious disease.

England

While in the three other nations of the UK, the health services are accountable to the devolved government, the central UK government is responsible for the NHS in England, where there are considerably greater restrictions in access.

Undocumented migrants and refused asylum seekers are entitled to access all health care services if doctors deem it clinically urgent or immediately necessary to provide it. However, the Home Office’s ‘hostile environment’ policies towards undocumented migrants, implemented aggressively and without training for clinical staff, are leading to the inappropriate denial of urgent and clearly necessary care.

One example is the case of Elfreda Spencer, whose treatment for myeloma was delayed for one year, allowing the disease to progress, resulting in her death.

In England, these policies, which closely link health care and immigration enforcement, are also deterring people from seeking health care they are entitled to. For example, medical bills received by migrants contain threats to inform immigration enforcement of their details if balances are not cleared in a certain timeframe. Of particular concern, the NGO Maternity Action has demonstrated that such a link to immigration officials results in the deterrence of pregnant women from seeking care during their pregnancy.

Almost all leading medical organizations in the United Kingdom have raised concerns about these policies, highlighting the negative impact on public health and the lack of financial justification for their implementation. Many have highlighted that undocument migrants use just and estimated 0.3% of the NHS budget and have pointed to international evidence that suggests that restrictive health care policies may cost the system more.

Australia

In Australia, all people who seek refuge by boat are held, and have their cases processed offshore in Papua New Guinea (PNG) and Nauru, at a cost of almost A$5 billion between 2013 and 2017. Through this international agreement, in place since 2013, Australia has committed to arrange and pay for the care for the refugees, including health services ‘to a standard of care broadly comparable to that available to the general Australian community under the public health system’.

However, the standard of care made available to the refugees is far from comparable to that available to the general population in Australia. Findings against the current care provision contractor on PNG, Pacific International Hospital, which took over in the last year, are particularly damning.

For instance, an Australian coroner investigating the 2014 death from a treatable leg infection of an asylum seeker held in PNG concluded that the contractor lacked ‘necessary clinical skills’, and provided ‘inadequate’ care. The coroner’s report, issued in 2018, found the company had also, in other cases, denied care, withheld pain relief, distributed expired medication and had generally poor standards of care, with broken or missing equipment and medication, and services often closed when they were supposed to be open.

This has also been reiterated by the Royal Australasian College of Physicians, which has appealed to the Australian government to end its policies of offshore processing immediately, due to health implications for asylum seekers. This echoes concerns of the medical community around the government’s ongoing attempts to repeal the ‘Medivac’ legislation, which enables emergency medical evacuation from PNG and Nauru.

Bad policy

Both governments have signed up to UN Sustainable Development Goals commitment to ‘safe and orderly migration’, an essential component of which is access to health care. The vision for this was laid out in a global action plan on promoting the health of refugees and migrants, agreed by member states at the 2019 World Health Assembly.

However, rather than allow national policies to be informed by such international plans and the evidence put forward by leading health professionals and medical organizations, the unsubstantiated framing of migrants as a security risk and economic burden has curtailed migrant and refugee access to health care.

The inclusion of migrants and refugees within universal access to health services is not merely a matter of human rights. Despite being framed as a financial burden, ensuring access for all people may reduce costs on health services through prevention of costly later-stage medical complications, increased transmission of infections and inefficient administrative costs of determining eligibility.

Thailand provides an example of a middle-income country that recognized this, successfully including all migrants and refugees in its health reforms in 2002. Alongside entitling all residents to join the universal coverage scheme, the country also ensured that services were ‘migrant friendly’, including through the provision of translators. A key justification for the approach was the economic benefit of ensuring a healthy migrant population, including the undocumented population.

The denial of quality health services to refugees and undocumented migrants is a poor policy choice. Governments may find it tempting to gain political capital through excluding these groups, but providing adequate access to health services is part of both governments’ commitments made at the national and international levels. Not only are inclusive health services feasible to implement and good for the health of migrants and refugees, in the long term, they are safer for public health and may save money.





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The single CCA-adding enzyme of T. brucei has distinct functions in the cytosol and in mitochondria [RNA]

tRNAs universally carry a CCA nucleotide triplet at their 3'-ends. In eukaryotes, the CCA is added post-transcriptionally by the CCA-adding enzyme (CAE). The mitochondrion of the parasitic protozoan Trypanosoma brucei lacks tRNA genes and therefore imports all of its tRNAs from the cytosol. This has generated interest in the tRNA modifications and their distribution in this organism, including how CCA is added to tRNAs. Here, using a BLAST search for genes encoding putative CAE proteins in T. brucei, we identified a single ORF, Tb927.9.8780, as a potential candidate. Knockdown of this putative protein, termed TbCAE, resulted in the accumulation of truncated tRNAs, abolished translation, and inhibited both total and mitochondrial CCA-adding activities, indicating that TbCAE is located both in the cytosol and mitochondrion. However, mitochondrially localized tRNAs were much less affected by the TbCAE ablation than the other tRNAs. Complementation assays revealed that the N-terminal 10 amino acids of TbCAE are dispensable for its activity and mitochondrial localization and that deletion of 10 further amino acids abolishes both. A growth arrest caused by the TbCAE knockdown was rescued by the expression of the cytosolic isoform of yeast CAE, even though it was not imported into mitochondria. This finding indicated that the yeast enzyme complements the essential function of TbCAE by adding CCA to the primary tRNA transcripts. Of note, ablation of the mitochondrial TbCAE activity, which likely has a repair function, only marginally affected growth.




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What will an ETF listed under Nasdaq Rule 5704 need to submit to Nasdaq to evidence compliance with the continued listing standards?

Publication Date: Apr 10 2020 Funds listed under Nasdaq Rule 5704 are required to submit an annual certification regarding the funds compliance with Rule 6c-11 during the most recent fiscal year. The certification is required within 30 calendar days of a fund’s fiscal year end. The certification can be found here....




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The Executive Director's Statement to the 150th Meeting of the Committee of Permanent Representatives

In these unusual and tragic times, I am indeed grateful that we are able to connect virtually to continue the business of environmental governance. While the efforts of all your capitals are correctly focused on preventing human suffering, as parts of the world move slowly towards recovery, the environmental agenda remains one of our most powerful insurance policies in preventing future global pandemics like COVID-19.




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Report of the fifth meeting of the Compliance Committee now available.




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Report of the sixth meeting of the Compliance Committee now available.




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Summary Outcomes of the Fifth Meeting of the BCH Informal Advisory Committee (BCH IAC). The BCH IAC provides guidance regarding the technical issues associated with the ongoing development of the BCH.




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Report of the eighth meeting of the Compliance Committee




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Report of the ninth meeting of the Compliance Committee under the Cartagena Protocol




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The Report of the Compliance Committee under the Cartagena Protocol on Biosafety on the Work of Its Tenth Meeting is now available.




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The summary outcomes of of the ninth meeting of the Informal Advisory Committee on the Biosafety Clearing-House is now available.




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The report of the twelfth meeting of the Compliance Committee under the Cartagena Protocol on Biosafety is now available.




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The report of the fourteenth meeting of the Compliance Committee under the Cartagena Protocol on Biosafety is now available.




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CBD News: The "Green Wave" launched at the UN Bonn Biodiversity Summit.




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CBD News: Biodiversity added to the agenda of Hokkaido Toyako G8 Summit. G8 Environmental Ministers issue the "Kobe Call for Action for Biodiversity".




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CBD News: World Leaders Redouble Their Commitment to Fulfil the Commitment of Heads of State and Government to Substantially Reduce the Rate of Loss of Biodiversity by 2010.




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CBD Biodiversity: A Missing Link for Mitigating Climate Change - World Environment Day celebrated in Montreal.




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CBD News: Japan launches the preparation of the Nagoya Biodiversity Summit to be held in Aichi Prefecture, Nagoya city in October 2010.




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CBD News: Statement by Executive Secretary, Ahmed Djoghlaf, on the occasion of the World Cities Summit, Singapore, 23-25 June 2008.




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CBD News: G8 Hokkaido Toyako Summit - A Historic Contribution to Biodiversity.




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CBD News: State of Parana delivers on its Commitment to offset Carbon Emissions of the Operations of the CBD Secretariat.




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CBD News: Statement by the Executive Secretary Mr. Ahmed Djoghlaf on "Biodiversity challenges and responses: Towards the Nagoya Summit on Biodiversity" at the Sixteenth Environment Congress for Asia and the Pacific, 14 September 2008, Nagoya, Ja




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CBD News: Asia and Pacific leads in preparing for 2010 Nagoya Biodiversity Summit.




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CBD News: Statement by Ahmed Djoghlaf, Executive Secretary of the Convention on Biological Diversity to the Second Committee at the Sixty-Third Session of the General Assembly of the United Nations, New York, 27 October 2008.




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CBD News: Statement by the Executive Secretary, Dr. Ahmed Djoghlaf, at the 28th meeting of the Standing Committee of the Bern Convention, Strasbourg, France, 24 November 2008.